7-carboxymethyloxy-3′,4′,5-trimethoxy flavone represented by formula 2 has been known to have mucus protecting activity in gastrointestinal tract including colon (WO 98/04541, Korea Patent No. 96-30494). This flavone showed therapeutic effects on gastrointestinal diseases such as gastritis or gastric ulcer, and inflammatory intestinal diseases such as ulcerative colitis or Crohn's disease.

The present inventors discovered that 7-carboxymethyloxy-3′,4′,5-trimethoxy flavone represented by the above formula 2 is hygroscopic. Each dose of a medicine should include a specified amount of an active compound. However, in case the active compound is hygroscopic, meaning tendency to absorb moisture from atmosphere, it is not easy to make the metered dose correspond to the specified amount of the active compound consistently. And also a hygroscopic material give rise to the difficulty in handling and storage condition. That is, the characteristic as a hygroscopic material is a big disadvantage for the production as a medicine. Thus, the present inventors have tried hard to find a stable form of the active ingredient without hygroscopicity.
A synthetic method for 7-carboxymethyloxy-3′,4′,5-trimethoxy flavone was described in WO 98/04541 (Korea Patent No. 96-30494), as shown in scheme 1 consisting of 9 step-total synthesis started from 2,4,6-trihydroxy acetophenone.

This synthetic method is useful for the production of the derivatives of various different substituents. But 2,4,6-trihydroxy acetophenone used as a starting material is so expensive that it is not economical for the industrial production, furthermore considering long 9 step reaction and low yield make the matters worse. In order to eliminate benzyl group used for a protecting group of hydroxyl, the hydrogen gas under pressure in the presence of palladium catalyst (Pd/C) was used twice in Scheme 1. For this hydrogenation reaction a special device to handle the pressured gas is necessary and palladium catalyst is also very expensive, making the processes complicate and uneconomical. The industrial use of hydrogen gas and catalyst is also dangerous.
Another preparation method for 7-carboxymethyloxy-3′,4′,5-trimethoxy flavone was described in Korea patent No. 99-41205, as shown in scheme 2.

In the above processes, a compound of formula 3 was reacted with methylating reagent under the basic condition. Conversion of hydroxyl groups in carbon-3′ and carbon-5 of the formula 3 into methoxy groups followed by acid treatment furnished a compound of formula 3a. The mixture of 3′,5,7-trihydroxy-4′-methoxy flavone-7-rutinoside of formula 3 in dimethylformamide, potassium carbonate and iodomethane were stirred in closed vessel at 60° C. for 48 hours, leading to the conversion of hydroxyl groups of carbon-3′ and carbon-5 of formula 3 into methoxy groups. After treating the resultant compound with acid gave the compound of formula 3a.
Then, hydroxyl group of carbon-7 of the compound of formula 3a was converted into alkyloxycarbonylmethyloxy group to give a compound of formula 3b. The deprotection of carboxyl group furnished a compound of formula 2.
The methylation mentioned above needs a special device and is dangerous because the reaction must be carried out in a closed vessel causing huge pressure. So the mass-production of a compound becomes inefficient. In order to give the compound of formula 3b from the compound of formula 3a, purification with column chromatography was inevitable. Therefore, the above preparation method invites danger and high cost.
Thus, the present inventors discovered that 7-carboxymethyloxy-3′,4′,5-trimethoxy flavone.monohydrate is a non-hygroscopic compound which is more suitable for the preparation of metered dose than 7-carboxymethyloxy-3′,4′,5-trimethoxy flavone.anhydride, and established a synthetic method thereof which is more economical, convenient and adequate for mass-production as well as devoid of costly purification procedure of column chromatography.